Indene derivatives as pharmaceutical agents

Abstract

Compounds of formula (Ia): wherein R 1 , R 2 , R 3 , R 4a , R 4b , R 5 , and R 6 are defined herein, as well as other indene derivatives are disclosed herein. Pharmaceutical compositions containing the compounds and methods of using the compounds are also disclosed.

What is claimed is: 
     
       1. A compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein: 
         the A, C or D ring is independently fully saturated, partially saturated or fully unsaturated; 
         C1, C4, C11, C12, C15 and C16 are each independently optionally substituted with one or two of the following, which are independently selected: hydrogen, alkyl, —R 8 —OR 7 , or —R 8 —N(R 7 ) 2 , provided that C4 is not substituted by two methyl groups; 
         C9 and C14 are each independently optionally substituted with hydrogen, alkyl, —R 8 —OR 7 , or —R 8 —N(R 7 ) 2 ; 
         R 1  is —OR 7  or —N(R 7 ) 2 ; 
         R 2  and R 3  are each independently selected from the group consisting of —R 8 —OR 7 , —R 8 —OC(O)R 9 , —R 10 —N(R 7 ) 2 , —R 10 —N(R 9 )C(O)R 9 , —R 10 —N(R 9 )S(O) t R 9  (where t is 1 or 2), —R 10 —N(R 9 )C(NR 9 )N(R 9 ) 2 , alkyl, alkenyl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted heterocyclylalkyl, optionally substituted heteroarylalkyl and optionally substituted heteroarylalkenyl; 
         R 4a  is hydrogen and R 4b  is alkenyl or alkynyl; 
         or R 4a  and R 4b  are each alkyl; 
         R 5  is alkyl or a direct bond to the carbon at C14, provided that when R 4a  is hydrogen and R 4b  is alkenyl or alkynyl, R 5  is alkyl and when R 4a  and R 4b  are both alkyl, R 5′  is a direct bond to the carbon at C14; 
         R 6  is hydrogen, —R 8 —OR 7  or —R 8 —N(R 7 ) 2 ; 
         each R 7  is independently selected from the group consisting of hydrogen, —R 10 —OR 9 , —R 10 —N(R 9 ) 2 , alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl; 
         each R 8  is independently selected from the group consisting of a direct bond, a straight or branched alkylene chain, and a straight or branched alkenylene chain; 
         each R 9  is independently selected from the group consisting of hydrogen, alkyl, aryl and aralkyl; and 
         each R 10  is independently selected from the group consisting of a straight or branched alkylene and a straight or branched alkenylene chain; 
         as a single stereoisomer, a mixture of stereoisomers, or as a racemic mixture of stereoisomers; 
         or a pharmaceutically acceptable salt, solvate or prodrug thereof, in isolation or in a mixture. 
       
     
     
       2. The compound of  claim 1  having the following formula (Ia): 
       
         
           
           
               
               
           
         
         wherein: 
         the A, C or D ring is independently fully saturated or partially saturated; 
         C1, C4, C11, C12, C15 and C16 are each independently optionally substituted with one or two hydrogens; 
         C9 and C14 are each independently substituted with hydrogen; 
         R 1  is —OR 7  or —N(R 7 ) 2 ; 
         R 2  and R 3  are each independently selected from the group consisting of —R 8 —OR 7 , —R 8 —OC(O)R 9 , —R 10 —N(R 7 ) 2 , —R 10 —N(R 9 )C(O)R 9 , —R 10 —N(R 9 )S(O) t R 9  (where t is 1 or 2), —R 10 —N(R 9 )C(NR 9 )N(R 9 ) 2 , alkyl, alkenyl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted heterocyclylalkyl, optionally substituted heteroarylalkyl and optionally substituted heteroarylalkenyl; 
         R 4a  is hydrogen and R 4b  is alkenyl or alkynyl; 
         or R 4a  and R 4b  are each alkyl; 
         R 5  is alkyl or a direct bond to the carbon at C14, provided that when R 4a  is hydrogen and R 4b  is alkenyl or alkynyl, R 5  is alkyl and when R 4a  and R 4b  are both alkyl, R 5′  is a direct bond to the carbon at C14; 
         R 6  is hydrogen, —R 8 —OR 7  or —R 8 —N(R 7 ) 2 ; 
         each R 7  is independently selected from the group consisting of hydrogen, —R 10 —OR 9 , —R 10 —N(R 9 ) 2 , alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl; 
         each R 8  is independently selected from the group consisting of a direct bond, a straight or branched alkylene chain, and a straight or branched alkenylene chain; 
         each R 9  is independently selected from the group consisting of hydrogen, alkyl, aryl and aralkyl; and 
         each R 10  is independently selected from the group consisting of a straight or branched alkylene and a straight or branched alkenylene chain; 
         as a single stereoisomer, a mixture of stereoisomers, or as a racemic mixture of stereoisomers; 
         or a pharmaceutically acceptable salt, solvate or prodrug thereof. 
       
     
     
       3. The compound of  claim 2  wherein:
 R 1  is —OR 7 ; 
 R 2  is —R 8 —OR 7 ; 
 R 3  is selected from the group consisting of —R 8 —OR 7 , —R 8 —OC(O)R 9 , —R 10 —N(R 7 ) 2 , —R 10 —N(R 9 )C(O)R 9 , —R 10 —N(R 9 )S(O) t R 9  (where t is 1 or 2), —R 10 —N(R 9 )C(NR 9 )N(R 9 ) 2 , alkyl, alkenyl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted heterocyclylalkyl, optionally substituted heteroarylalkyl and optionally substituted heteroarylalkenyl; 
 R 4a  is hydrogen and R 4b  is alkenyl or alkynyl; 
 or R 4a  and R 4b  are each alkyl; 
 R 5  is alkyl or a direct bond to the carbon at C14, provided that when R 4a  is hydrogen and R 4b  is alkenyl or alkynyl, R 5  is alkyl and when R 4a  and R 4b  are both alkyl, R 5′  is a direct bond to the carbon at C14; 
 R 6  is hydrogen, —R 8 —OR 7  or —R 8 —N(R 7 ) 2 ; 
 each R 7  is independently selected from the group consisting of hydrogen, —R 10 —OR 9 , —R 10 —N(R 9 ) 2 , alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl; 
 each R 8  is independently selected from the group consisting of a direct bond, a straight or branched alkylene chain, and a straight or branched alkenylene chain; 
 each R 9  is independently selected from the group consisting of hydrogen, alkyl, aryl and aralkyl; and 
 each R 10  is independently selected from the group consisting of a straight or branched alkylene and a straight or branched alkenylene chain. 
 
     
     
       4. The compound of  claim 3  which is 5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcyclohexyl)-4α-aminomethyl-7aβ-methyl-1β-(propen-2-yl)octahydroindene. 
     
     
       5. The compound of  claim 3  which is 5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcyclohexyl)-4α-aminomethyl-1,1-dimethyl-2,3,4,5,6,7-hexahydro-1H-indene, or a pharmaceutically acceptable salt thereof. 
     
     
       6. The compound of  claim 5  wherein the pharmaceutically acceptable salt is a pharmaceutically acceptable acid addition salt formed from an inorganic or organic acid. 
     
     
       7. The compound of  claim 6  wherein the inorganic or organic acid is selected from:
 hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid or undecylenic acid. 
 
     
     
       8. The compound of  claim 5  which is 5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcyclohexyl)-4α-aminomethyl-1,1-dimethyl-2,3,4,5,6,7-hexahydro-1H-indene. 
     
     
       9. The compound of  claim 5  which is 5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcyclohexyl)-4α-aminomethyl-1,1-dimethyl-2,3,4,5,6,7-hexahydro-1H-indene, ammonium chloride salt. 
     
     
       10. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of  claim 1 , as a single stereoisomer, a mixture of stereoisomers, or as a racemic mixture of stereoisomers; or a pharmaceutically acceptable salt, solvate or prodrug thereof, in isolation or in a mixture.